Age, Sex, and Depot‐Specific Differences in Adipose‐Tissue Estrogen Receptors in Individuals with Obesity

Abstract

Objective The aim of this study was to examine the effects of sex and menopausal status on depot‐specific estrogen signaling in white adipose tissue (AT) in age‐matched men and women with morbid obesity. Methods A total of 28 premenopausal women, 16 postmenopausal women, and 27 age‐matched men undergoing bariatric surgery were compared for omental (OM) AT (OMAT) and abdominal subcutaneous (SQ) AT (SQAT) genes and proteins. Results With the exception of fasting nonesterified fatty acids being higher in women (P < 0.01), no differences were found in other indicators of glucose and lipid metabolism. In OMAT, estrogen receptor (ER) beta (ERβ) levels were higher in older women than in younger women and older men (sex‐age interaction, P < 0.01), and aromatase expression was higher in older men than in older women (P < 0.05). In SQAT, women had lower expression of ERβ than men (P < 0.05). Protein content of ER alpha and ERβ was highly correlated with the mitochondrial protein uncoupling protein 1 across sexes and ages (P < 0.001). Age increased SQ inflammatory gene expression in both sexes. Conclusions In morbid obesity, sex and age affect AT ERs, lipid metabolism, mitochondrial uncoupling protein 1, and inflammatory expression in an AT depot–dependent manner. The SQAT immunometabolic profile is heavily influenced by age and menopause status, more so than OMAT.

White Adipose Tissue Depots Respond to Chronic Beta-3 Adrenergic Receptor Activation in a Sexually Dimorphic and Depot Divergent Manner

“…BAT expresses high levels of its signature thermogenic protein, uncoupling protein 1 (UCP1), which we have shown repeatedly to be metabolically beneficial in both males and females [ 23 , 24 ]. Moreover, we and others have shown robust sex differences in the basal expression of WAT UCP1, with females expressing higher levels [ 9 , 25 , 26 ].…”

“…The underlying physiological and biochemical mechanisms responsible for this sexual dimorphism are unknown; however, many are thought to be exerted through estrogen (E2) signaling pathways [ 6 , 7 , 8 ]. E2 primarily signals through estrogen receptor alpha (ERα) and ER beta (ERβ), both of which are expressed in adipose tissue [ 9 , 10 ], as well as many other cell types in both sexes [ 11 ]. Thus, understanding the role these ERs play in both males and females is vital to the study of metabolic disease.…”

Estrogens and the regulation of glucose metabolism

“…Both ERα and ERβ are dimeric and coded by different genes[ 96 , 97 ], with an additional abundance of polymorphisms[ 98 , 99 ]. Their distribution in the cells of different tissues and organs is independent for each receptor[ 100 ], as are their final gene expression effects[ 101 , 102 ]. They can show synergic[ 103 ] or antagonistic[ 104 ] effects, even for the same molecular species, and depend, largely, on the post-binding relationships of the E2-ER complex.…”

Hypothalamic Estrogen Signaling and Adipose Tissue Metabolism in Energy Homeostasis

“…Sex-specific distribution of adipose tissue has been described in humans and animal models. Females are more abundant in sWAT, while males tend to have more abdominal-visceral depots ( 79 , 80 ). Males have evolved to store highly metabolically active visceral fat depots that can be quickly mobilized and used as energy fuel under short-term energetic challenges such as hunting.…”

“…Depletion of ERα in the mouse brain abolishes the beneficial metabolic effects of estrogen, resulting in hyperphagia, body weight gain, increased visceral adiposity, and impaired energy expenditure ( 17 , 20 , 59 , 103 ). In human adipose tissue, expression of ERα is positively associated with UCP1 protein density ( 80 ). Similarly, adipose tissue ERα expression in mouse is correlated with lower adiposity, higher UCP1 content, optimal BAT thermogenic function, and insulin sensitivity ( 104 ).…”